N- -piperazine

To the Wang resin (100 mg, 0.070 mmol) in a 3-mL polypropylene filtration tube with polyethylene frit was added 1 mL 0.4 N CDI in anhydrous THF (note 1), capped with a yellow polyethylene cap, and shaken at room temperature for 6 h (note 2). The resin was thoroughly washed with CH2C12 (3x1 mL) and THF (3x1 mL) to remove the excess CDI and then treated with 1 mL 0.4 N piperazine in THF at room temperature for 15 h. The resulting resin was washed with DMF (3x1 mL), MeOH (4x1 mL),... 

N-N -Piperazine- 0 0 -ethylaraime acid dihydroohloride, 40. y-Piperazinopropylarsinic acid dihydroohloride, 42. p-Piperidinoethylarsinic acid, 40. 

B) Secondary amines, (i) Aromatic amines. Monomethyl and monoethylaniline, diphenylamine. (ii) Aliphatic and other amines. Diethyhmine, di-n-propylamine, di-isopropylamine. Also piperidine piperazine diethylene-diamine). 

Piperazine, I -diethyIcarbamyI-4-methyl-metabolism, 1, 227 Piperazine, N,JV-dimethyI-epoxy resin curative. 1, 406 Piperazine, 2,5-dioxo-occurrence, 3, 187 Piperazine-2,5-dione polymers, 1, 298... 

Heavy metal contamination of pH buffers can be removed by passage of the solutions through a Chelex X-100 column. For example when a solution of 0.02M HEPES [4-(2-HydroxyEthyl)Piperazine-l-Ethanesulfonic acid] containing 0.2M KCl (IL, pH 7.5) alone or with calmodulin, is passed through a column of Chelex X-100 (60g) in the K" " form, the level of Ca ions falls to less than 2 x 10" M as shown by atomic absorption spectroscopy. Such solutions should be stored in polyethylene containers that have been washed with boiling deionised water (5min) and rinsed several times with deionised water. TES [, N,N, -Tetraethylsulfamide] and TRIS [Tris-(hydroxymethyl)aminomethane] have been similarly decontaminated from metal ions. 

Depending upon the structure of the substrates 49, 52, and 56 hexahydropyrido[l,2-n]-[3,l]benzoxazines 50, 54, 2-aminobenzaldehyde 53, 1-substituted piperidones 51, 55, 57, 3,4,5,6-tetrahydropyridinium salt 58, or their mixture was obtained during the oxidation of 1-(2-hydroxymethyl-, 2-formyl- and 2-acetylphenyl)piperazines (49, 52, 56) with Hg(II)-EDTA complex (Schemes 6-8) (79AP219, 98ZN(B)37, 98ZN(B)1369). 

Alteration of the structural pattern produces a pair of adrenergic a-blocking agents which serve as anti hypertensives. These structures are reminiscent of prazoci n. Reaction of piperazine with 2-furoy1 chloride followed by catalytic reduction of the furan ring leads to synthon 69. This, when heated... 

A variety of inorganic (31,87) and organic bases have been added to the catalyst to improve selectivity. The effectiveness of organic bases is very sensitive to structure. Morpholine is an effective inhibitor, more so than /Si-melhylmorphollne > N-elhylmorpholine > 3,5-dimethylmorpholine (55). Piperazine is effective, but ethanolamine and ethylenediamine are poisons. 

The mixture was stirred for 2 hours, heated at 60° to 70°C for 1 hour and poured into 2 liters of H O. The resulting suspension was extracted with ether, the ether layer separated and the ether removed under vacuum. A gummy mass remained which was dissolved in decalin and the solution was partly distilled to remove excess chlorobromide. After removal of most of the decalin under vacuum, the residue was treated with a large excess of N-( -hydroxyethyl)-piperazine and heated on a steam bath for 2 hours. This material was extracted with dilute aqueous HCI, this acid layer neutralized with aqueous base and the resulting oil extracted into ether. The ether layer was washed with water until the washings were neutral and dried over anhydrous potassium carbonate. On treatment with maleic acid in ether a yellow solid separated which was recrystallized from isopropanol. This yellow solid had MP 175° to 177°C. 

O.OB mol (19 g) of 4-chlorobenzhydryl chloride and 0.16 mol (16g) of methylpiperazine were mixed in about 20 cc of dry benzene. The flask containing the reaction mixture was covered by a watch glass and set in a steam bath, and heating was continued for 6 hours. The contents of the flask were partitioned between ether and water and the ethereal layer was washed with water until the washings were neutral. The ethereal layer was extracted successively with 30-and 10-cc portionsof 3 N hydrochloric acid. On evaporation of the ether layer there remained a residue of 2.5 g. The aqueous extracts were united and basified with concentrated alkali. The oily base was taken into ether and dried over potassium carbonate. On evaporation of the ether, N-methvl-N -(4-chlorobenzhvdryl) piperazine was recovered in the form of a viscous oil in 75% yield. The N-methvl-N -(4-chlorobenzhvdryl) piperazine was dissolved in absolute alcohol and ethanolic hydrogen chloride added in excess. The dihydrochloride crystallized... 

A mixture of 31 5 g (0.1 mol) of 2-chloro-9-(3 -dimethylaminopropylidene)-thiaxanthene (MP 97°C) and 100 g of N-( 3-hydroxyethyl)-piperazine is heated to 130°C and boiled under reflux at this temperature for 48 hours. After cooling, the excess of N-( 3-hydroxyethyl)-piperazine Is evaporated in vacuo, and the residue is dissolved in ether. The ether phase is washed with water and extracted with dilute acetic acid, and 2-chloro-9-[3 -N-(N - -hydroxy-ethyD-piperazinylpropylidene] -thiaxanthene separated from the aqueous acetic acid solution by addition of dilute sodium hydroxide solution to basic reaction. The free base is extracted with ether, the ether phase dried over potassium carbonate, the ether evaporated and the residue dissolved in absolute ethanol. By complete neutralization of the ethanolic solution with a solution of dry hydrogen chloride in absolute ethanol, the dihydrochloride of 2-chloro-9-[3 -N-(N -(3-hydroxyethyl)-piperazinylpropylidene] -thiaxanthene is produced and crystallizes out as a white substance melting at about 250°C to 260°C with decomposition. The yield is 32 g. 

One-tenth mol (20 g) of benzhydryl chloride was mixed with 0.19 mol (19 g) of N-methyl-piperazine and about 10 cc of benzene and the whole was heated on the steam bath four hours. The contents of the flask was partitioned between ether and water, and the ethereal layer was washed with water until the washings were neutral. The base was then extracted from the ethereal layer by N hydrochloric acid and the extract, made acid to Congo red paper, was evaporated under vacuum, 29.5 g of the pure dihydrochloride of N-methyl-N -benzhydryl piperazine was recovered from the residue by recrystallization from 95% alcohol melting above 250°C with decomposition. 

Triethylamine hydrochloride is separated by filtration and the filter cake is washed with 100 cc of anhydrous ethyl alcohol. The alcohol and the excess of triethylamine is distilled off in a vacuum of a water pump. The residue represents a light-yellowish brown viscous oil which is extracted 3 times with 500 cc of anhydrous benzene each time with stirring at 40° to 60°C. The benzene is distilled off on a water bath at 60°C. Thus, an oil is obtained which solidifies to a hard mass after some hours. This mass is crushed and dried over PjOs in an exsiccator. The compound represents N,N -bis-(3-hydroxypropyl)homo-piperazine. Yield 128.5 grams. FP 46°-47°C BPo.o2mm 141°-142°C. 

A mixture of 0.1 mol of N-mono-1-p-chlorobenzohydrylpiperazine and 0.1 mol of 1-chloro-2-(2-hydroxy-ethoxy)-ethane is heated for 3 hours to 150°C. The mass is then taken up in 100 ml of benzene and 100 ml of a 10% aqueous solution of NaOH decanting takes place, and the benzene solution is washed with water and the solvent is evaporated. Vacuum distilling of the residue yields 1-p-chlorobenzohydryl-4-[2-(2-hydroxy-ethoxy)-ethyl]-piperazine, BP 220 C/0.5 mm Hg. 

Chemical Name 4-[4,4-Bis(4-fluorophenyl)butvU -N-(2,6-dimethylphenyl)-1-piperazine-acetamide... 

A mixture of 65 parts 1 -[4,4-di-(4-fluoro-phenvl)butyl] -piperazine, 4.33 parts N-(2-chloro-acetyl)-2,6-dimethyl-aniline, 3.2 parts sodium carbonate, a few crystals of potassium iodide in 200 parts 4-methyl-2-pentanone is stirred and refluxed for 70 hours. After cooling there are added 70 parts water. The organic layer is separated, dried over potassium carbonate, filtered and evaporated. The oily residue is dissolved in 80 parts diisopropyl-ether and the solution is filtered hot. After cooling the filtrate at 0°C, the formed solid is filtered off and recystallized from 80 parts ether, yielding 1-[4,4-di-(4-fluoro-phenyl)butyl] -4-[(2,6-dimethyl-anilino-carbonvl)-mathyl] -piperazine MP 159°Cto 161°C. 

Chemical Name 8-Nitro-1,2-dihydro-2-(N-methyl-piperazin-1 -yl)methylene-6-(o-chloro-phenyl)-1 H,4H-imidazo-[ 1,2-a] [ 1,4] -benzodiazepin-1 -one methanesulfonate... 

Chamical Nama N-3-(2-Trifiuoromethyl-10-phenothia2inyl)-propyl-N -2-[2-(1,3-dioxanyl)]-ethyl-piperazine disuccinate... 

N-[2-(3,1 -DioxanyDethyl] piperazine 1 -Bromo-3-chloropropane 2-Trifluoromethylphenothiazine Sodium Succinic acid... 

Preparation of N-(3-chlorQpropyl)-N -[2-(1,3-dioxanyl)-ethyl]-piperazine A solution of 30 g... 

The sodium derivative of the 2-trifluoromethylphenothiazine was prepared from 26.7 g (0.1 mol) of 2-trifluoromethylphenothiazine and 2.3 g (0.1 g atom) of sodium in 500 ml of liquid ammonia. After the reaction was completed, the ammonia was driven off and 500 ml of dry toluene were added. A solution of 25 g (0.09 mol) of N-(3-chloropropyl)-N -[2-(1,3-dioxanyl)-ethyl] -piperazine In 200 ml of toluene was added drop by drop to this solution which was then refluxed with stirring for 1B hours. After cooling, the precipitate which had formed was filtered and the filtrate was washed with water, dried and concentrated in vacuo. 33 g of brown oil, the N-3-(2-trifluoromethyl-10-phenothiazinyl)-propyl-N -2-[2-(1,3-dioxanyl)] -ethyl-piperazine, were obtained. 

To this acid was then added 1 g of 4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride (from the reaction of N-ethylethylenediamine and diethyl oxalate to give 2,3-dioxo-4-ethyl-piperazine which Is then reacted with phosgene) and the resulting mixture was reacted at 15°C to 20°C for 2 hours. After the reaction, a deposited triethylamine hydrochloride was separated by filtration, and the filtrate was incorporated with 0.4 g of n-butanol to deposit crystals. The deposited crystals were collected by filtration to obtain 1.25 g of white crystals of 6-[ D(—l-Ct-(4-ethyl-2,3-dioxo-1 -piperazinocarbonylaminolphenylacetamido] penicillanic acid. Into a solution of these crystals in 30 ml of tetrahydrofuran was dropped a solution of 0.38 g of a sodium salt of 2-ethyl-hexanoic acid in 10 ml of tetrahydrofuran, upon which white crystals were deposited. The deposited crystals were collected by filtration, sufficiently washed with tetrahydrofuran and then dried to obtain 1.25 g of sodium salt of 6-[D(—)-a-(4-ethyl-2,3-di-0X0-1-piperazinocarbonylaminolphenylacetamido] penicillanic acid, melting point 183°C to 185°C (decomposition), yield 90%. 

To a solution of 17.2g (0.10 mol) of 3-bromopropionyl chloride in 100 ml of anhydrous benzene was added dropwise with stirring a solution of 8.6 g (0.10 mol) of anhydrous piperazine in 20 ml of dry chloroform over a period of 30 minutes. The temperature rose spontaneously to 45°C during the addition. After the temperature ceased to rise, stirring was continued for another hour. The reaction mixture was then filtered to remove the piperazine hydrochloride by-product. The filtrate was evaporated to dryness and the residue recrystallized from ethanol to obtain the desired N,N -bis-(3-bromopropionyl) piperazine as a white crystalline sol id melting at 103°C to 104°C. The identity of the product was further established by elemental analysis. 

---